Cerebroarthrodigital syndrome: A newly recognized formal genesis syndrome in three patients with apparent arthromyodysplasia and sacral agenesis,brain malformation and digital hypoplasia

We describe three patients with a complex syndrome of apparent arthromyodysplasia, dyscephaly, sacral agenesis, and hypoplastic digits. Cause is unknown, but an environmental cause is suspected on the basis of ergotamine exposure in one case and diazoxide intake in another, together with suggestive similarities to anomalies seen in animals treated with these drugs and to calves with the Australian hydranencephaly/arthrogryposis syndrome caused by Akebane or Aino virus. Pathogenetically the primary defect may be a neural tube-neural crest dysplasia with multiple secondary and tertiary manifestations and deformities.     

The Borjeson-Fbrssman-Lehmann syndrome

The propositus of this report presents a peculiar dysmorphic syndrome associated with severe mental retardation and epileptic attacks. Morphological stigmata include a round, fatty face with large, somewhat protruding tongue, large normally formed ears, relative microcephaly, abundant abdominal fat, dwarfism with hyperkyphosis and short neck. Analogous phenotypic abnormalities were present in the mother and a maternal cousin. The clinical and familial findings in this apparently rare mental retardation syndrome with apparently X-linked dominant or autosomal dominant inheritance with variable expression and penetrance are discussed.     

小头畸形产前诊断与管理的研究进展

 小头畸形是指胎儿头围明显小于同孕龄胎儿正常头围,可能是一种正常变异,也可能是神经系统畸形的标志。目前临床缺乏统一的诊断标准,不同原因以及不同程度的小头畸形预后差别很大,其中环境暴露和遗传因素是小头畸形最常见的原因。近年来,随着影像学及二代测序技术的快速发展,小头畸形的产前诊断水平相应提高。本综述比较了小头畸形不同诊断标准的差异,分析小头畸形的病因,包括感染的流行病学、传播及临床特征,并重点对小头畸形的产前诊断及孕期管理的相关研究进展进行了综述。     

Expanding the phenotype of RTTN variations: a new family with primary microcephaly,severe growth failure,brain malformations and dermatitis

Primary autosomal recessive microcephaly (MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing (WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c.2953A>G;pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out‐of‐frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism (PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN‐associated diseases and ciliary dysfunction.     

Three additional de novo CTCF mutations in Chinese patients help to define an emerging neurodevelopmental disorder

CCCTC‐binding factor (CTCF) is an important regulator for global genomic organization and gene expression. CTCF gene had been implicated in a novel disorder characterized by intellectual disability, feeding difficulty, developmental delay and microcephaly. So far, four patients have been reported with de novo CTCF mutations. We reported three additional Chinese patients with de novo variants in CTCF. The new evidence helped to establish the clinical validity between CTCF and the emerging disorder. We described the consistent phenotypes shared by all patients and revealed additional clinical features such as delayed or abnormal teeth development and a unique pattern of the eyebrow that may help to define a potential recognizable neurodevelopmental disorder. We also reported the first CTCF patient treated with recombinant human growth hormone. Follow‐up and more case studies will further our understanding to the clinical presentations of this novel disorder and the prognosis of patients with this disorder.     

FAM160B1 deficit associated with microcephaly,severe intellectual disability,ataxia, behavioral abnormalities and speech problems

Intellectual disability (ID) varies in severity and is often associated with a variety of other clinical features. In consanguineous populations ID is usually inherited in an autosomal recessive fashion. Many genes are known for the condition, but many more are yet to be identified. By linkage analysis and exome sequencing we identified homozygous early truncating variant c.115G > T (p.Glu39*) in FAM160B1 in a 38-year-old woman with severe ID, microcephaly, behavioral abnormalities, speech problems, mild ataxia and mild facial dysmorphism. Recently homozygous missense c.248 T > C (p.Leu83Pro) was reported to underlie the ID syndrome in a 7-year-old boy and his two younger siblings. Some findings for those siblings overlap with those for our patient, but our patient does not have cutis laxa. Our findings confirm FAM160B1, with unknown function, as a syndromic ID gene and indicate that FAM160B1 is not essential for survival but is vital for proper functioning of the nervous system, delineate the FAM160B1-related ID, and describe the disease in a much older age.     

Delineation of MidXq28-duplication syndrome distal to MECP2 and proximal to RAB39B genes

Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features. The duplications overlapped for 108 kb including FLNA, RPL10 and GDI1 genes, highly expressed in brain and candidates for the neurologic phenotype.     

The potential contribution of impaired brain glucose metabolism to congenital Zika syndrome

The Zika virus (ZIKV) became a major worldwide public concern in 2015 due to the congenital syndrome which presents the highest risk during the first trimester of pregnancy and includes microcephaly and eye malformations. Several cellular, genetic and molecular studies have shown alterations in metabolic pathways, endoplasmic reticulum (ER) stress, immunity and dysregulation of RNA and energy metabolism both in vivo and in vitro. Here we summarise the main metabolic complications, with a particular focus on the possibility that brain energy metabolism is altered following ZIKV infection, contributing to developmental abnormalities. Brain energetic failure has been implicated in neurological conditions such as autism disorder and epilepsy, as well as in metabolic diseases with severe neurodevelopmental complications such as Glut‐1 deficiency syndrome. Therefore, these energetic alterations are of wide‐ranging interest as they might be directly implicated in congenital ZIKV syndrome. Data showing increased glycolysis during ZIKV infection, presumably required for viral replication, might support the idea that the virus can cause energetic stress in the developing brain cells. Consequences may include neuroinflammation, cell cycle dysregulation and cell death. Ketone bodies are non‐glycolytic brain fuels that are produced during neonatal life, starvation or fasting, ingestion of high‐fat low‐carbohydrate diets, and following supplementation with ketone esters. We propose that dietary ketones might alter the course of the disease and could even provide some degree of prevention of ZIKV‐associated abnormalities and potentially related neurological conditions characterised by brain glucose impairment.